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“Sonographic fetal findings with borderline significance and Down Syndrome”

“Sonographic fetal findings with borderline significance and Down Syndrome”. Micaela Della Torre, MD MS Maternal Fetal Medicine. Objectives.

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“Sonographic fetal findings with borderline significance and Down Syndrome”

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  1. “Sonographic fetal findings with borderline significance and Down Syndrome” Micaela Della Torre, MD MS Maternal Fetal Medicine

  2. Objectives • Learn how to recognize the most common sonographic signs associated with trisomy 21 in the second trimester to improve recognition of affected fetuses • Learn sensitivity, specificity and likelihood ratios of the different signs • Learn how to better use genetic ultrasound in the contest of maternal screening test

  3. I declare that I do not have a financial interest or other relationship with any manufacturers of any commercial products that may be discussed during this presentation

  4. Outlines • Screening for Down syndrome and risk assessment • NT • NB, tricuspide regurgitation, abnormal ductusvenosus • cystic hygroma • Pyelectasis • Hyper-echoic bowel • Ventriculomegaly • Single umbilical artery • Long bones • Others

  5. “Observations on an ethnic classification of idiots” by Langdon Down in 1866 …The hair is not black, as in the real Mongol, but of a brownish color, straight and scanty. The face is flat and broad, and destitute of prominence. The cheeks are roundish, and extended laterally. The eyes are obliquely placed, and the internal canthi more than normally distant from one another. The palpebral fissure is very narrow. The forehead is wrinkled transversely from the constant assistance which the levatores palpebrarum derive from the occipito-frontalis muscle in opening of the eyes. The lips are large and thick with transverse fissures. The tongue is long, thick, and is much roughened. The nose is small. The skin has a slight dirty yellowish tinge, and is deficient in elasticity, giving the appearance of being too large for the body.’ …

  6. Last three decades major improvement in pregnancy screening for open neural tube defect (ONTD) and aneuploidy • Now screening primarily for adjusted risk of chromosomal abnormality • T18 and T21 • Better detection rate of ONTD by ultrasound alone

  7. Chromosomal defects: frequency and occurrence • Natural frequency for chromosomal abnormalities at birth is estimated to be 6:1000 • Most common is trisomy 21 (overall 1:700) • The risk of Down syndrome varies drastically w maternal age • USA • women 35-49 of age • 4.7% of live births in 1974 • 12.6% of live births in 1997

  8. Down syndrome • Three separate mechanisms • Non disjunction (95%) • 95% of non disjunction is maternal in origin • Translocation • Mosaicism

  9. Maternal and paternal age risk • Relationship between age and increased risk was first noticed by Penrose in 1933 • Prevalence also increases w paternal age • Fathers more than 39 of age have 3 times higher risk than in father less than 35 of age • True even if adjusted for maternal age Lansacet al 1997 Jalbert 1995

  10. 1970s  maternal age alone • Predictive value of maternal screening alone is poor • lower than 25% • 1 affected fetus over 125 invasive procedures • Even worst now that the proportion of pregnant women over 35 is increasing • Screening protocols allow detection of trisomy21 among younger women and better assessment of the risk in older women

  11. 1980s – more tools were introduced to better assess the risk of Down syndrome • maternal age • concentration of various fetoplacental products in the maternal circulation (maternal biochemistry) • a-fetoprotein, estriol, human chorionic gonadotropin (hCG) (total and free-b) • method of screening is more effective than maternal age alone

  12. 1990s • Maternal age • Fetal nuchal translucency thickness at 11–14 weeks of gestation • PPV 75% w FP rate 5% • Even more recently • Maternal age • Fetal nuchal translucency • Maternal serum biochemistry • free b-hCG • PAPP-Aabout 90% • PPV 90% w FP rate 5% • Now different options are available

  13. Down syndrome detection • First trimester • levels of PAPP-A and free -hCG • NT • Detection rate of 85% with 5% false positive rate (FPR) • Second trimester quad screen • levels of AFP, hCG, estriol, and inhibin A • Detection rate of 81% with 5% FPR • Step-wise sequential • Detection rate of 95% with 5% FPR

  14. Nuchal translucency • Szabo and Gellen were the first to describe an abnormal nuchal translucency in the first trimester as a marker for Down’s syndrome Lancet 1990

  15. Technique • CRL 39 to 84mm • Sagittal view - magnification should be such that the fetus occupies at least three-quarters of the image • Careful distinguish between fetal skin and amnion • NT should be measured with the fetus in the neutral position – • Hyperextension increase up to 0.6mm • Flexion decrease up to 0.4mm • If umbilical cord is around the neck the NT measurements can be falsely increased

  16. Summary of reported series on fetal NT and presence of associated chromosomal defects – early 90s

  17. Late 1990,s - detection rate

  18. More recent detection rates

  19. Counseling • Both first trimester and sequential screening have been established as reliable risk assessment tools • Especially if NT is less than 95th percentile • Invasive testing should be offered to all cases of increased NT (3 to 3.5 mm) • If karyotype is normal, fetal echocardiogram should be obtained • FISH for 22q11.2 deletion • If karyotype is normal, normal outcome is expected in more than 85% of cases

  20. Prevalence of major cardiac defects in normal chromosome fetuses w increased NT – Hyett et al 1996

  21. Other markers… • Further improvements in screening performance may be achievable in the future • Nasal Bone • Tricuspid regurgitation by pulsed wave Doppler • Abnormal blood flow through the ductus venosus • ADAM 12 – placental glycoprotein

  22. Nasal bone • Cicero 2001 and 2003 • NB appears to be absent in about 68% of fetuses w Down’s syndrome • Absent only in 1-2% of normal fetuses • No correlation w biochemical markers • DR 96% and FPR 5% • DR 90% and FPR 1% • Technical difficulties • Altered incidence in Afro-Caribbean populations – Cicero 2004

  23. Tricuspid regurgitation • Hurron 2003 • Tricuspid regurgitation is present in 8% of normal fetuses and in 65% of T21 fetuses • Independent from serum markers • Falcon 2006 • Combined MA/NT/Serum and tricuspid regurgitation • 95% DR and 5% FPR (90% DR and 2-3% FPR)

  24. Abnormalductusvenosus • Ductusvenosus is fetal shunt between the portal vein and inferior vena cava • Oxygenated blood from placenta to the heart • Very useful in assessing fetal abnormal cardiac function

  25. Abnormal ductus venosus flow • Mattias et al 1998 • Perform ductus venosus Doppler in fetuses with increased NT • Abnormal ductus in 57 of 63 (90.5%) chromosomally abnormal fetuses • Abnormal ductus in 13 of 423 (3.1%) chromosomally normal fetuses • 7 of 13 with absent or reversed flow had major cardiac defect demonstrated 14–16 weeks

  26. Nicolaides, K.H.(2005). The 11-13+6 weeks scan. pp 72.

  27. What is this?

  28. Intracardiac echogenic focus • Micro-calcification within the papillary muscle of the heart • 0.5 to 20% - mostly in left ventricle, but it can be right or bilateral • Caucasians 3.5 to 10.5% • AA 5.5 to 5.9% • Asians 10 to 30% • Isolated in low risk population – no increased risk • Likelihood ratio 1.8 – rarely a low risk patient becomes an high risk patient • High risk population or associated with other findings – addition counseling is warranted

  29. What is it?

  30. Single Umbilical Artery • 0.5-2% of all prenatal ultrasound • caucasian 3 times higher than AA • very rare in Japanese descent • 3 to 4 fold increase in twins • Targeted imaging to rule out concurrent anomalies (15-45% associated anomalies) • If other anomalies not seen in utero, 7-10% chance of findings at birth • Associated anomalies-high risk aneuploidy (20-25% to 45% if CNS anomalies) • Isolated SUA in AGA fetus- risk aneuploidy age related - Parilla et al 1995 • Some literature suggest slight increase, approximately 1%

  31. 2 vessels cord • IUGR in as high as 28% of cases of isolated single umbilical artery • Placental anomalies found in 16 to 78% of cases • Most common small placenta and abnormal cord insertion • Perinatal mortality increased after adjustment for associated anomalies

  32. What is it?

  33. Mild pelviectasis • Distention of fetal renal pelvis by urine • Most often bilateral, when unilateral right more common than left • Up 16% associated with other anomalies • < 4 mm, < 33 weeks • < 7 mm, > 33 weeks • > 10 mm is always pathologic • Common finding – 2-3% in normal fetuses • More common in male than female 2:1 • Trisomy 21 – likelihood 1.6 • Risk of Uropathy • UPJ obstruction, VUR, primary nonrefluxingmegaureter, UVJ obstruction, ectopic ureter, PUV, magacysticmegaureter, physiologic dilatation, multicystic dysplastic kidneys, ARPKD, extrophy, prune belly syndrome

  34. Counseling • Increased risk of Down syndrome • If not screening test available, risk is about 1% • If screening test is available, risk is increased slightly compared adjusted maternal risk • Amniocentesis • Repeat ultrasound after 32 weeks

  35. Counseling • 30-50% of fetuses with isolated pyelectasis will have normal postnatal course • Vast majority of affected fetuses do not require surgical intervention (99%) • Consider neonatology and pediatric urology evaluation at time of birth • (tertiary center??, evaluation can be delayed to day 2-3 of life)

  36. What is it?

  37. Echogenic bowel • Non specific finding • Bowel should have echogenicity similar to bone structures • Gain setting down until other soft tissue cannot be seen – only echogenic bowel and bones • Nyberg classification • Grade 1 moderate diffuse echogenicity • Grade 2 focal echogenicity (more likely to be associated with problems) • Grade 3 very echogenic , as bone

  38. Most cases of isolated finding do have normal outcomes • Simon-Bouy 2003 • Prospective study of 682 cases • 447 normal outcome (65.5%)

  39. Can be associated with GI anomalies • bowel atresia, anorectal malformations, volvulus, obstruction (2-10%) • CF (2-4%) • Viral infection (3-4%) – CMV, Toxoplasmosis, Parvo B19 • Down syndrome

  40. Aneuploidy risk • Bansiak et al 2001 • Cumulative 9.5% aneuploidy (63/663) • Isolated 3% (13/439) and DS was the most common • Simon Bouy et al 2003 • Cumulative 4.3% (29/682) • Shipp et al 2002 • Increase 5.5 times the a priori risk for DS • Nyberg et al 2001 • Likelihood ratio for DS 6.7 if isolated hyperechoic bowel

  41. Poor obstetrical outcomes • Rochon and Eddleman 2004 • 14-18% of pregnancies complicated by echogenic bowel also experience growth restriction and IUGR • Increased risk of IUFD and neonatal death • Simon-Bouy 2003 • 2% unexplained IUFD • Amniocentesis, CF screening, TORCH • Serial ultrasound • ANT

  42. What is it?

  43. Ventriculomegaly • Width of the atria of the lateral ventricles >10mm • Mild 10-12 • Severe >15 • 1-2/1000 • Trisomy 13,18,21; triploidy, umbalanced translocations (4%) • Normal variant • Congenital infection – toxoplasmosis, CMV, syphylis • Absence corpus callosum • Hydrocephalus – aqueductalstenosis, ONTD, Dandy Walker

  44. Age-adjusted ultrasound risk assessment for trisomy 21 Nyberg1998 • AAURA is a priori risk (MA) X LR resulting from presence or absence of specific US findings for each patient • Lilelihood ratio = sensitivity / false-positive rate as an isolated finding • Case-control study • 142 fetuses with trisomy 21 and 930 fetuses with normal karyotype • All patients underwent 2nd trimester US at single institution through standardized US protocol w/o knowledge karyotype

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